This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic, 08-AR-101: Genotyping of Existing Cohorts in Rheumatic, Skin, and Musculoskeletal Diseases. These studies will utilize existing clinical cohorts to create a broadly shared data resource that is currently missing in this important disease area and we will make this resource available to all researchers. The immediate result of the work will be submission of a large genotype-phenotype dataset, consisting of >3,000 cases of Juvenile Idiopathic Arthritis (JIA), to the Database of Genotypes and Phenotypes (dbGaP). This database will allow our collaborative working group and others to pursue analytical projects that will identify genetic loci contributing to disease risk. The datasets will also provide access to results derived from our own new methodological analytical approaches aimed at the identification of genetic risk factors for JIA. JIA is the #1 cause of acquired disability in children, afflicting one in every one thousand children. Recent reports, including our own, have identified genetic variants common to multiple subtypes of inflammatory arthritis (e.g., seropositive adult rheumatoid arthritis, systemic JIA, polyarticular JIA). These genes could represent "master switches" predisposing to arthritis in general, in concert with other genes that contribute to phenotypic subtype. This project seeks to elucidate the genetic underpinnings of JIA by genotyping a large well-phenotyped population. Accordingly, in Stage 1 of our Specific Aim, we propose to define JIA candidate regions with evidence for association in a discovery cohort of 1,500 JIA cases recruited from the greater Philadelphia area and collaborating international centers. Approximately 50% of this cohort is already genotyped and this funding will enable us to augment this dataset by whole genome-wide association (GWA) analyses of over 700 additional samples (all of which are already in-hand), using a high-density single nucleotide polymorphism (SNP)-based design to track 600,000 potential polymorphisms. In Stage 2, we will replicate our findings by selective genotyping of an additional 1,000 existing samples from well-phenotyped JIA cases recruited to other collaborating sites. This database will be leveraged against matched samples from a collection of over 8,000 genotyped controls, from which we expect at least 4,000 to be a perfect match. We hypothesize that the association of genome-wide individual SNPs, SNP haplotypes, or CNVs with JIA will identify candidate risk genes and structural variants that predispose to JIA. This Challenge project will create or retain 4 jobs and will buy American-made products. Juvenile idiopathic arthritis (JIA) is the #1 cause of acquired disability in children. Our project seeks to identify important genes that, when altered, put a child at high-risk for JIA, in turn suggesting new targets for drugs to improve outcomes for these children.